Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis.

BACKGROUND: Postmarketing commitments are clinical studies that pharmaceutical companies agree to conduct at the time of FDA approval, but which are not required by statute or regulation. As FDA increasingly adopts a lifecycle evaluation process, greater emphasis will be placed on postmarket evidence as a component of therapeutic evaluation. Therefore, the objectives of this study were to determine how often postmarketing commitments agreed upon by pharmaceutical companies at first FDA approval lead to new clinical trials and to establish the characteristics and rates of completion and dissemination of postmarketing commitments. METHODS: For new drugs and biologics approved in 2009-2012, we used public FDA documents, ClinicalTrials.gov, and Scopus, to determine postmarketing commitments and their characteristics known at the time of FDA approval; number subject to reporting requirements, for which FDA is required to make study status information available to the public ("506B studies"), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials. RESULTS: Among 110 novel drugs and biologics approved by the FDA between 2009 and 2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 33 (10.0%) were for new clinical trials; 27 of these were 506B studies subject to public reporting requirements, of which 12 (44.4%) did not have a recent (i.e., up-to-date) or closed (i.e., fulfilled or released) status provided publicly by the FDA. Although two postmarketing commitments were insufficiently described in FDA records to perform searches on ClinicalTrials.gov, nearly all (28, 90.3%) of the 31 remaining postmarketing commitments for new clinical trials were registered on ClinicalTrials.gov. Among the registered trials, 23 (23 of 28, 82.1%) were classified as completed or terminated, of which 22 (95.7%) had reported results. When considering all 29 completed or terminated clinical trials, registered or unregistered on ClinicalTrials.gov, only half (14, 48.3%) were published in peer-reviewed journals. CONCLUSIONS: While only 15% of postmarketing commitments agreed to by pharmaceutical companies at the time of FDA approval were for new clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, only half were published, and despite FDA public reporting requirements, recent status information was often unavailable for 506B studies.

Age-treatment subgroup analyses in Cochrane intervention reviews: a meta-epidemiological study.

BACKGROUND: There is growing interest in evaluating differences in healthcare interventions across routinely collected demographic characteristics. However, individual subgroup analyses in randomized controlled trials are often not prespecified, adjusted for multiple testing, or conducted using the appropriate statistical test for interaction, and therefore frequently lack credibility. Meta-analyses can be used to examine the validity of potential subgroup differences by collating evidence across trials. Here, we characterize the conduct and clinical translation of age-treatment subgroup analyses in Cochrane reviews. METHODS: For a random sample of 928 Cochrane intervention reviews of randomized trials, we determined how often subgroup analyses of age are reported, how often these analyses have a P < 0.05 from formal interaction testing, how frequently subgroup differences first observed in an individual trial are later corroborated by other trials in the same meta-analysis, and how often statistically significant results are included in commonly used clinical management resources (BMJ Best Practice, UpToDate, Cochrane Clinical Answers, Google Scholar, and Google search). RESULTS: Among 928 Cochrane intervention reviews, 189 (20.4%) included plans to conduct age-treatment subgroup analyses. The vast majority (162 of 189, 85.7%) of the planned analyses were not conducted, commonly because of insufficient trial data. There were 22 reviews that conducted their planned age-treatment subgroup analyses, and another 3 reviews appeared to perform unplanned age-treatment subgroup analyses. These 25 (25 of 928, 2.7%) reviews conducted a total of 97 age-treatment subgroup analyses, of which 65 analyses (in 20 reviews) had non-overlapping subgroup levels. Among the 65 age-treatment subgroup analyses, 14 (21.5%) did not report any formal interaction testing. Seven (10.8%) reported P < 0.05 from formal age-treatment interaction testing; however, none of these seven analyses were in reviews that discussed the potential biological rationale or clinical significance of the subgroup findings or had results that were included in common clinical practice resources. CONCLUSION: Age-treatment subgroup analyses in Cochrane intervention reviews were frequently planned but rarely conducted, and implications of detected interactions were not discussed in the reviews or mentioned in common clinical resources. When subgroup analyses are performed, authors should report the findings, compare the results to previous studies, and outline any potential impact on clinical care.

Transparency of Regulatory Data across the European Medicines Agency, Health Canada, and US Food and Drug Administration.

Based on an analysis of relevant laws and policies, regulator data portals, and information requests, we find that clinical data, including clinical study reports, submitted to the European Medicines Agency and Health Canada to support approval of medicines are routinely made publicly available.

Analysis of Postapproval Clinical Trials of Therapeutics Approved by the US Food and Drug Administration Without Clinical Postmarketing Requirements or Commitments.

Importance: The US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval. Objective: To characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments. Design, Setting, and Participants: This cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018. Main Outcomes and Measures: Postapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting. Results: From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date. Conclusions and Relevance: Pharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.

Mild exercise in female subjects impairs complex learning independent of hydration status and emotion.

INTRODUCTION: Depending on type, intensity and duration, exercise can have both beneficial and detrimental effects on cognitive function. The impact of exercise on learning and memory is also sensitive to hydration status, so we hypothesized that mild hypohydration induced with exercise, will adversely impact executive and complex memory function tasks and that these changes in cognitive function are independent of changes in emotion. METHODS: Using a cross over design, on separate days 11 women exercised on a recumbent bicycle. On day 1, women exercised to 1.5% hypohydration at 34°C, and <10% rh, on day 2, water loss from sweating was replaced by drinking water (euhydration). Pre- and post-euhydration and hypohydration, subjects underwent computer based cognitive tasks (simple, learning, memory, executive function) and visual analog testing to determine emotion. RESULTS: Exercise increased Groton Maze Learning Test errors within both conditions: [Pre: 41.5±11.8, Post: 46.8±12.4, and Pre: 41.9±9.2, Post: 46.5±12.9, hypohydrated and euhydrated, respectively, Pre vs Post, ANOVA, time effect, P=0.007], a test of acquisition, storage, and use of new knowledge. None of the measures of emotion were affected by exercise under either hydration condition. CONCLUSIONS: A bout of mild aerobic exercise compromised performance on a complex learning and memory task, but this change was unaffected by hydration status or emotion.